CS257797B2 - Method of (4,5,6r,8r)-methyl-9-oxo-11 alpha,15 alpha-dihydroxy-16 phenoxy-17,18,19,20-tetranorprosta-4,5,13(e)-trienoat's crystalline form preparation - Google Patents

Abstract

This invention relates to a process for making a compound of formula I in the form of a stereoisomer or mixture thereof, wherein R is hydrogen, lower alkyl; X is hydrogen, halo, trifluoromethyl, lower alkyl or lower alkoxy, and the wavy lines represent the a or β configuration with the proviso that when one wavy line is α the other is β, or a pharmaceutically acceptable, non-toxic salt of the compound wherein R is hydrogen; novel intermediates useful for preparing these compounds; processes for making the intermediates; and a stereoisomer of the compound of formula I wherein R is methyl and X is hydrogen and a process for making same.

Description

U.S. Patent No. 4,178,457 discloses compounds of Formula I

where

R represents hydrogen, lower alkyl, X represents hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy and the wavy line represents the a or β configuration, provided that when one of them is a, the other β, or a pharmaceutically acceptable salt thereof wherein R is hydrogen and the stereoisomers of those compounds of formula (I) wherein R is N 2 and X is hydrogen; a process for the preparation of these compounds is also disclosed.

The compounds of U.S. Pat. No. 4,178,457 are useful in treating mammals in the indication of prostaglandins. They are particularly suitable as gastric secretion inhibitors. It has been found that the stereoisomer of a compound of formula I having the R-alleric configuration, wherein R is methyl and X is hydrogen, having the following formula Г

- f 1 '6'

it has excellent biological properties (eg efficacy, low toxicity, etc.) and other properties that affect its pharmaceutical use (chem. stability, applicability, etc.). Experiments conducted in rats have shown that the antisecretory ED 50 for this R-allenic stereoisomer is about 6 µg / kg.

Prostaglandins are often in the form of oily substances. A racemic diastereoisomeric mixture of compounds of formula I wherein R is methyl and X is hydrogen is known as a viscous oil (see US Patent No. 4,178,457) or a low melting waxy solid. Compound that is structurally closest to the R-allene stereoisomer of Formula (A) and its racemic diastereoisomeric mixtures, i.e., (d1) 9a, 11a, 15a-trihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4 methyl ester, 5.13 (E) -triene (the compound in Example 16 of US Patent No. 3,985,791) also occurs in oily form. The R-allene stereoisomer of formula Г was first obtained also in oily form, but when stored in a freezer to stabilize the substance, it was surprisingly found that spontaneous crystallization occurred. This crystalline substance has a melting point above 70 ° C. In contrast to this isomer, the corresponding diastereoisomeric mixture when stored in the freezer under the same conditions for 1 to 3 weeks becomes a waxy substance. The S-allene stereoisomer corresponding to formula nikdy never crystallized under similar conditions.

Further, U.S. Patent No. 1,288,174, U.S. Patent No. 4,005,133 and EPO Publication No. 97,439 disclose that they need to be converted to their organic or inorganic salts to obtain crystalline solid iprostiaglandins. Therefore, it is also surprising that the R-allene stereoisomers of formula (A) crystallize without being converted to the free salt.

Accordingly, the present invention provides a process for preparing the crystalline form of (4,5,6R, 8R) -methyl-9-oxo-11a, 15α-dihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13 ( E) -trienoate of formula I ⁴

characterized in that the oily compound of formula (I) above is cooled to a temperature of -20 to 0 ° C.

The crystalline compound of formula Г can be readily purified using conventional techniques. The crystallinity of this substance facilitates handling, chemical analysis and improves chemical stability, moreover, the crystalline substance of formula Г can be easily formulated into solid preparations.

The broken bond means that the substituent is below the plane of the allene group and is referred to as the α-configuration. A triangular bond means that the substituents are above the plane of the allene group and are referred to as the β-configuration.

The use of the R symbol before a substituent means the absolute stereochemical configuration of this substituent according to the Cahn-IngoldPrelog rules [see Cahn et al., Angew. Chem. Inter. Edit., Vol. 5, p. 385 (1966), errata p. 511; Cahn et al. Angew.

Chem., Vol. 78, p. 413 (1966); Cahn and In 257797 gold, J. Chem. Soc. (London), 1951, p. 612;

Cahu et al., Experientía, Vol. 12, p. 81 (1956); Cahn J. Chem. Educ., Vol. 41, p.

116 (1964)]. _t

The R-isomer of formula (A) is exceptionally useful in the treatment and prevention of gastric and duodenal ulcers.

The R-allene isoimers of formula Г can be administered in various dosage forms either alone or in combination with other pharmaceutically compatible drugs in the form of pharmaceutical preparations suitable for oral or parenteral administration, or by inhalation when used as bronchodilators. Typical uses of this agent are administration in the form of a pharmaceutical composition comprising substantially said compound and a pharmaceutical carrier. The pharmaceutical carrier may be either a solid, a liquid or an aerosol in which the taro compound is dissolved, dispersed or suspended and may contain small amounts of preservatives and / or buffering agents. A suitable preservative is, for example, benzyl alcohol and the like. Suitable buffering agents are, for example, sodium acetate and pharmaceutically acceptable phosphate salts or the like.

The liquid preparations may be, for example, preparations administered in the form of solutions, emulsions, suspensions, syrups, elixirs. The solid preparations may take the form of tablets, powders, capsules, pills, and the like, preferably in unit dosage form, for reasons of single administration and accurate dosing. Suitable solid carriers include, for example, pharmaceutically acceptable starch, lactose, saccharin sodium, talc, sodium hydrogen sulfide and the like.

For administration by inhalation, the R-allene isomers of formula Г can be administered, for example, in the form of an aerosol consisting of this compound in a suitable inert propellant together with a cosolvent such as methanol, together with suitable preservatives and buffering agents. Further general information regarding aerosol inhalation may be obtained from U.S. Patent Nos. 2,868,691 and 3,095,355.

The precise effective dose of the R-allene isomers of Formula I will greatly depend on the route of administration, the treatment conditions, and the condition of the patient.

The invention is further illustrated by the following non-limiting examples.

Example 1

Crystalline (4,5,6R, 8R) -methyl-9-oxo-11tt, 15α-dihydroxy-16-phenoxy-17,18,19,20-tetrainorprosta-4,5,13 (E) -trienoate

Approximately 720 mg of (4,4,6R, 8R) -methyl-9-oxo-11a ', 15α-dihydroxy-16-phenoxy-17,18,19,20-tetrahydro-piperazine-4,5,13 ( E) -trienoate oil is placed in a freezer where the oily material crystallizes spontaneously. A sample (50 mg) of the solid material was purified very rapidly by flash chromatography, then crystallized from ethyl acetate / hexane to give acicular crystals, m.p. 71-71.5 ^° C. The purity of the substance by HPLC was 98%.

Example 2

Biological activity of (4,5,6R, 8R) -methyl-9-oxo-11α, 15α-dihydroxy-16-phenoxy-17,18,19,20-tetra-norprosta-4,5,13 (E) - Trienoate (determination of histamine-induced gastric juice secretion)

Male Spraque-Dawley rats (Hilltop) were used in the experiment. The animals were fastened around the neck with a round plastic collar to prevent food or faeces from being consumed and to empty the stomach during the 48-hour starvation period. The above compound was administered orally via a probe in the morning at the beginning of the experiment, 30 minutes before surgery. During this procedure, the animals were anesthetized with ether and on the duodenum, one ligature was placed close to the pyloric clamp, the other on the posterior portion of the esophagus and larynx. The laparotomy was closed with staples and 40 mg / kg histamine diphosphate was injected successively once during the 3-hour period of acid gastric secretion monitoring. After 3 hours, the rats were sacrificed, the contents of the stomach aspirated and the volume measured. An aliquot of gastric juice was filtered on a pH meter with 0.02N sodium hydroxide until pH 7.0 + + 0.1. The amount of gastric juice excreted in milliequivalents per 100 g body weight was calculated. Statistical comparisons of the observed groups of animals with the control groups were performed. In this test, (4,5,6R, 8R) -methyl-9-oxo-11a, 15α-dihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13 (E) -trienoate , at doses of 0.5 to 4 µg / kg, an extrapolated ED 50 of 6 µg / kg was found.

Example 3

(4,5,6R, 8R) -Methoxy-9-oxo-11a, 15α-dihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13 (E) -trienoate (4) 5,6R, 8R) -methyl-9-oxo-11a, 15α-dihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13 (E) -trienoate was administered to male mice (sim (ICR / FBR) intraperitoneally in an amount of 0.125 to 0.5 mg / kg. No mortality was observed.

Claims (1)

Process for preparing crystalline form of (4,5,6R, 8R) -methyl-9-oxo-11a, 15α-dlhydroxy-16-phenoxy-17,18,19,20-tetranorpnosta-4,5,13 (Ej-trienoate of formula Г BACKGROUND OF THE INVENTION characterized in that the oily compound of formula (I) above is cooled to -20 to 0 ° C.